Genetic Switch Turns White Fat to Beige Fat

Scientists developing weight-loss drug based on study results

Action Points

Note that this mouse study seems to have identified a genetic "switch" that can convert energy-storing white fat cells to energy-burning beige fat cells.

Be aware that these findings relied on genetic manipulation of the target gene -- whether pharmacologic intervention will lead to similar results is not yet known.

Researchers working with rodents found a genetic mechanism that caused fat cells to burn energy rather than store it, suggesting new possibilities for treating obesity, they reported.

Mice in which this genetic program was activated were 50% thinner than control mice, did not gain weight on a high-fat diet, and burned energy at a high rate even when sleeping, according to a team of international researchers writing in the Aug. 20 issue of the New England Journal of Medicine.

"By manipulating this new pathway, we could switch between energy storage and energy dissipation programs at both the cellular and organismal level, providing new hope for a cure against obesity," said senior investigator Manolis Kellis, PhD, of MIT in Boston, in a press release.

"FTO is highly expressed in the brain compared to other tissues, so scientists assumed that it acted in the brain. But we looked at more than a hundred human tissues and cell types and found that this region acts in adipocyte precursor cells," lead investigator Melina Claussnitzer, PhD, of Harvard Medical School, told MedPage Today.

"These are predetermined stem cells found in white adipose tissue. We found a huge regulatory element there," Claussnitzer said.

The researchers found that a single nucleotide variation in the FTO gene region disrupts the activity of a regulating gene called ARID5B. With the regulating effect of ARID5B disrupted, two other genes become highly expressed in adipocyte precursor cells. These two genes, IRX3 and IRX5, cause these cells to shift from energy-dissipating beige fat cells to energy-storing white fat cells.

By using gene editing technology to change one nucleotide in the FTO gene region -- in this case swapping a cytosine for a thymine -- the scientists were able to restore the function of ARID5B, reduce the expression of IRX3 and IRX5, and reverse the process in human primary adipocytes.

The cells increased their thermogenic activity by a factor of 7, the researchers reported. "This is the first study to correct a genetic variant and recover a complete phenotype," Claussnitzer said.

Mice in which the IRX3 gene was repressed in adipocytes were generated as well. "These mice had pronounced anti-obesity characteristics, including reduced body size, body weight, fat mass, white and brown fat depots, and adipocyte size," the investigators reported.

"The effect in these mice was dramatic. They lost half their body weight. They didn't gain an ounce on a high-fat diet. They burned energy without any kind of exercise or locomotor activity," Claussnitzer said.

Similarly, the investigators created mice in which the IRX5 gene was repressed. The group is saving that data for a future paper, Claussnitzer said, but the results were generally in line with the other experiments.

The obesity-associated variant of the FTO gene is common in humans. It affects 44% of Europeans, Claussnitzer said.

The investigators are already working to develop an anti-obesity drug based on their findings. They are screening for small molecules to target IXR3 and IXR5, and they are exploring viral delivery of small molecules or RNA, Claussnitzer said.

"This work has several implications, albeit with certain caveats," said Clifford Rosen, MD, of the Maine Medical Center Research Institute in Scarborough, and Julie Ingelfinger, MD, of Massachusetts General Hospital in Boston, in an accompanying editorial.

"The results support previous in vitro and in vivo studies indicating that browning of white adipose tissue has physiological relevance and that disorders of mitochondrial function and brown fat may play a role in pathophysiological aspects of obesity," they indicated.

"Shifting adipocytes from energy storage to energy expenditure with pharmacologic and nonpharmacologic measures may become feasible as the ARID5B-FTO-IRX3/IRX5 regulatory network becomes fully defined," Rosen and Ingelfinger wrote.

However, they cautioned, "as yet there is still no simple path to an anti-obesity drug that can be derived from this research."

This research was supported by the German Research Center for Environmental Health, the Heart and Stroke Foundation of Canada, the Canadian Institute of Health Research, the Western Norway Regional Health Authority, the Swedish federal government, and the U.S. National Institutes of Health.

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